A facile base-mediated synthesis of N-alkoxy-substituted benzimidazoles

Article abstract of DOI:10.1016/j.tet.2017.06.063

Base mediated cyclization of enamines derived from condensation of 2-nitroanilines with α-branched aldehydes, in the presence of an electrophile, affords N-alkoxy-substituted benzimidazoles with or without an oxygenate side chain in the 2-position.

Full text of DOI:10.1016/j.tet.2017.06.063

Accepted Manuscript
A facile base-mediated synthesis of N-alkoxy-substituted benzimidazoles
Nurul H. Ansari, Arica L. Jordan, Björn C.G. Söderberg
PII:
S0040-4020(17)30706-8
10.1016/j.tet.2017.06.063
TET 28828
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 May 2017
Revised Date: 22 June 2017
Accepted Date: 27 June 2017
Please cite this article as: Ansari NH, Jordan AL, Söderberg BjöCG, A facile base-mediated synthesis of
N-alkoxy-substituted benzimidazoles, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.063.
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ACCEPTED MANUSCRIPT
A facile base-mediated synthesis of N-alkoxy-substituted benzimidazoles
Nurul H. Ansari, Arica L. Jordan and Björn C. G. Söderberg*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West
Virginia 26506-6045, United States
Abstract
Base mediated cyclization of enamines derived from condensation of 2-nitroanilines with α-
branched aldehydes, in the presence of an electrophile, affords N-alkoxy-substituted
benzimidazoles with or without an oxygenate side chain in the 2-position.
Introduction
In an attempt to N-methylate enamine 1, the compound was dissolved in dimethylsulfoxide
(DMSO) and 3 equivalents of sodium hydride was added at ambient temperature (Scheme 1).
After mixing for 1 h, the resulting reaction mixture was cooled to 0 oC and 3.2 equivalents of
methyl iodide was added. After slowly warming to ambient temperature over 2 h, the reaction
mixture was worked up and purified by chromatography to give three different products. The
expected methylated product 2 was not isolated instead, 1-methoxybenzimidazole (3), 1-
methoxy-2-(2-methoxy-2-propyl)benzimidazole (4), and 1-methoxy-2-(2-hydroxy-2-
propyl)benzimidazole (5) were obtained in 5%, 57%, and 15% yield, respectively.
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Scheme 1. Formation of benzimidazoles 3-5 from enamine 1.
1
2 (not observed)
3 (5%)
4 (57%)
5 (15%)
The transformation of 1 to benzimidazoles 3-5 is related to base-mediated cyclizations of N-
phenacyl-2-nitroaniline1 and N-benzyl-2-nitroanilines to give N-oxygenated benzimidazoles.2
Gardiner and coworkers have developed and extensively utilized a more general methodology
for the formation of 2-substituted 1-alkoxybenzimidazoles employing 2-nitroanilines and
organic halides in the presence of a base (Scheme 2).3,4 In addition to Gardiners’ methodology, N-
alkoxybenzimidazoles can be prepared from N-hydroxybenzimidazoles either via a Williamson
type ethers synthesis5 or by a Mitsunobu reaction with an alcohol.6 Although relatively unusual,
N-oxygenated benzimidazoles have been shown to exhibit anti-protoza7 and anti-HIV activities.3d
Scheme 2. Cyclization of N-allyl-2-nitroaniline to give 2-ethenyl-N-propoxybenzimidazole.3f
The reaction of 1 to give 3-5 seen in Scheme 1 significantly differs from previously reported
cyclizations in that either a loss of or oxygenation of the side chain is observed. To the best of our
knowledge, no examples of N-alkoxy-2-(alkoxyalkyl)benzimidazoles or N-alkoxy-2-
(hydroxyalkyl)benzimidazoles have been reported to date. Herein we present a study of the
scope and limitation of the base mediated cyclization of enamines derived from 2-nitroanilines
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and α-branched aliphatic aldehydes to give N-oxygenated benzimidazoles. A plausible
mechanism for the reaction is also discussed.
Results and discussion
An initial set of experiments were carried out in an attempt to establish, if possible, optimal
reaction conditions for the selective formation of all three types of benzimidazole products (3-5
in Scheme 1) by simply varying the amount of base and alkylating reagent used. Thus, the
number of equivalents of sodium hydride and methyl iodide was systematically varied using
enamine 6 (Table 1). This substrate was selected in place of 1 in order to facilitate product ratio
determinations by 1H NMR of the crude products since the methoxy group situated on the
benzene ring offered an additional resonance for integration. Reaction of 6 with 1.05 equivalents
of both NaH and MeI did not furnish any appreciable amount of either of the possible products 7-
9 (Table 1, entry 1). A trace amount of 1,6-dimethoxybenzimidazole (7) was observed in the 1H
NMR spectrum of the crude reaction mixture. It should be noted that compound 7 was observed
in the crude product or isolated as an inseparable mixture with 2-(2-hydroxy-2-propyl)-1,6-
dimethoxybenzimidazole (9) in < 7% yield in all entries in Table 1 when DMSO was used as the
solvent (entries 1-9). Maintaining the amount of base at 1.05 equivalents and increasing the
amount of MeI to 2.10 equivalents resulted in the formation of benzimidazole 9 in moderate
yield in addition to a significant amount of unreacted enamine 6. The yield of 9 was not further
improved using 3.10 equivalents of MeI (entries 2-3). Gratifyingly, an almost exclusive formation
of alcohol 9 was observed in a reaction wherein the amount of base was increased to 2.10
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equivalents together with 1.05 equivalent of MeI (entry 4). From the results seen in entries 1-4, it
appears that N-O methylation is faster compared to C-O methylation since selective formation of
9 can be achieved using 1.05 equivalents of MeI. Addition of 2.10 equivalents of both NaH and
MeI resulted in the formation of the dialkylated product 1,6-dimethoxy-2-(2-methoxy-2-
propyl)benzimidazole (8) at the expense of 9 however, further increasing the amount of MeI did
not improve the yield of 8 or the overall yield of the reaction (entries 5-6). Finally, using 3.15
equivalents of both NaH and MeI resulted in a clean conversion of 6 to 8 with only trace amounts
of the other two benzimidazoles observed in the 1H NMR spectrum of the crude reaction mixture
(entry 7). It is interesting to note that three equivalents of base was also found to be the
optimum for the reaction forming 1-alkoxybenzimidazoles reported by Gardiner et al (Scheme
2).3b Further increase in the amount of base and alkylating reagent did not improve the yield of 8
(entry 9). In addition to DMSO, N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP),
and acetonitrile (MeCN) were examined as potential solvents for the cyclization however, only a
low yield of 8 was isolated in each case (entries 9-11). The formation of benzimidazole 7 was
observed in each case in yields ranging from trace amounts in NMP, 29% in DMF, and 65% in
acetonitrile.
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Table 1. Product distribution dependence on the equivalents of NaH and MeI and solvent used.
6
7
8
9
Entry
1b
Eq. NaH
1.05
Eq. MeI
1.05
Solvent
DMSO
DMSO
DMSO
Alkoxybenzimidazolesa
7c
2d
1.05
2.10
7 (~1%)
7 (~3%)
7 (~2%)
7 (~5%)
7 (~7%)
7c
9 (~34%)
9 (~30%)
9 (~74%)
9 (~56%)
9 (~46%)
9c
3e
1.05
3.17
4
5
6
7
2.10
2.10
2.10
3.15
1.05
2.10
3.16
3.15
DMSO
DMSO
DMSO
DMSO
8 (tr.)
8 (17%)
8 (18%)
8 (69%)
8
3.75
5.0
3.33
5.0
DMSO
DMSO
DMF
7 (~5%)
7c
8 (64%)
8 (65%)
8 (8%)
9 (~2%)
9
10
11
12
3.74
3.75
3.74
3.20
3.32
3.20
7 (21%)
7c
NMP
8 (29%)
8 (13%)
MeCN
7 (65%)
a) Isolated yields of pure products after chromatography unless stated as ~%. The ~% are yields calculated from the
1H NMR spectrum of an inseparable mixture. b) The starting material was recovered in 48% yield. c) Trace amount
of the compound was observed in the 1H NMR of the crude reaction mixture. d) The starting material was recovered
in 40% yield. e) The starting material was recovered in 35% yield.
The scope and limitation of the base-mediated cyclization to give N-oxygenated benzimidazoles
was probed using fifteen different enamines and the results of these reactions are summarized in
Table 2. In addition to ten previously reported enamines, five new enamines were prepared by
condensation of the appropriately substituted 2-nitroaniline with an aldehyde in
dichloromethane or benzene in the presence of molecular sieves. Enamines derived from
condensation of 2-nitroanilines bearing a substituent in the 4- or 5-position and 3-
methylpropanal were selected in order to evaluate the effects of electronic properties and the
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relative position of the substituent on the benzene ring in a systematic fashion without a
significant steric contribution (Table 2, entries 1-25). The enamines were subjected to two
different reaction conditions selected from Table 1 varying only in the stoichiometry of the
added reagents. experiments using 3.15 equivalents of both NaH and MeI to afford dimethylated
benzimidazoles are referred to as Conditions A (See Table 1, entry 7) and reactions using 2.1
equivalents NaH and 1.05 equivalents of MeI to give mono-methylated benzimidazoles as the
major product are referred to as Conditions B (See Table 1, entry 4). We initially considered
acetonitrile and the ratio of reagents seen in entry 12 in Table 1 to be plausible conditions for the
synthesis of 2H-N-alkoxybenzimidazoles. However, when applied to other enamines, complex
mixtures of products in inferior yields were obtained using these conditions.
The reactions of enamines with sodium hydride followed by addition of methyl iodide under
Conditions A are summarized in Table 2. As seen in the table, all substrates but the 4-nitro-
substituted enamine 23 furnish N-methoxybenzimidazole(s) under these conditions. Enamines
with a methoxy- (6), chloro- (10), bromo- (12), or fluoro- (15) group in the 4-position gave good
to excellent yields (69-94%) of dimethylated benzimidazoles as the only product isolated after
chromatography (Table 2, entries 1-8).
In each of the reactions, an immediate color change to deep purple was observed upon addition
of a solution of the enamine to a suspension of NaH in DMSO. In most cases, the purple color
rapidly changed to brown or orange-brown within two minutes. The brown color was indicative
of a “resting” state of the reaction and no further transformations would occur until the addition
of MeI. For example, addition of MeI either after 2 minutes or after 9 h of stirring at ambient
temperature gave almost identical isolated yields of 8 (entries 2-3). This sequence of color
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changes was observed for all substrates, although longer reaction times were required in some
cases before the purple color would disappear.
Apart from the selective reactions observed for the first four substrates in Table 2, the
experiments summarized in entries 9-29 gave either 2H-unsubstituted N-
methoxybenzimidazoles, mixtures of N-methoxybenzimidazoles, or N-methylation of the starting
material. For some substrates, different product patterns were obtained under Conditions A
depending on the time elapsed prior to addition of MeI and the addition temperature. The parent
enamine 1 and the 4-methyl- and 5-methyl-substituted analogs 17 and 32 produced mixtures of
three benzimidazoles when the addition of MeI was made at 0 oC (entries 9, 11, and 24). In
contrast, monoalkylated benzimidazoles (5, 20, and 35) were not observed when MeI was added
at ambient temperature (entries 10, 12, and 25). The reason for this difference in product
pattern is unclear.
Two substrates containing an electron-withdrawing group, a methyl ester (21) and a nitro group
(23), in the 4-position of the aromatic ring were examined (Table 2, entries 13-16). Treatment of
ester functionalized substrate 21 with NaH followed by addition of MeI, after 10 minutes at
ambient temperature resulted in N-methylation of the starting material in 62% yield. No
benzimidazole product was observed. However, allowing the substrate-base mixture to stir for
24 h prior to the addition of MeI furnished N-methoxybenzimidazole 22 in good isolated yield.
No trace of a 2-substituted benzimidazole was observed by 1H NMR of the crude reaction
mixture. Treatment of 23 gave in a similar fashion the product derived from N-methylation of the
starting material in 85% yield as the sole product upon addition of MeI after 1 h at 0 oC. In
contrast to ester derivative 21, extending the reaction time for the nitro analog 23 prior to
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addition of MeI did neither produce a benzimidazole or any other product nor was the starting
material recovered.
N-Methylation of the amino-group of the starting material was not limited to the electron-
deficient substrates 21 and 23 but was also observed when an insufficient amount of time was
given before the addition of MeI. For example, reaction of the 5-methoxy- and the 5-chloro-
substituted enamines 24 and 26 gave N-methylation of the amino group of the aniline as the
major or sole product (entries 17 and 19). However, extending the reaction time for the
substrate-NaH-DMSO mixture of 24 and 26 eliminated the amino-group methylation and N-
methoxybenzimidazoles were isolated (entries 18 and 20).
Two additional enamines 36 and 39, obtained from condensation of 4-methoxy-2-nitroaniline
with cyclohexane carbaldehyde and 4-bromo-2-nitroaniline with 2-phenylpropanal, respectively,
were also examined (Table 2, entries 26-29). The methoxy-substituted enamine 36 behaved
similar to 6, affording the expected di-alkylated benzimidazole 37. In addition, a minor amount
of the mono-alkylated benzimidazole 38 was isolated upon addition of MeI at ambient
temperature (entry 27). Finally, enamine 39 proved to be sensitive to the temperature for the
addition of MeI. All three previously encountered type of N-oxygenated benzimidazoles 13, 40,
and 41 were obtained each in low yield at 0 oC. In contrast, only 13 was obtained at ambient
temperature in excellent yield.
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Table 2. Base-mediated formation of benzimidazoles under Conditions A.
Entry Enamine
Temp/timea
Alkoxybenzimidazolesb
Σ (%)c
1
2
3
4
5
6
7
8
9
6 (R=4-OMe)
1 h - 0 oC
2 min - RT
9 h - RT
7d
7d
7d
8
8
8
(71%)
(71%)
(69%)
(71%)
(71%)
(69%)
(86%)
(94%)
(78%)
(93%)
(75%)
(85%)
(95%)
(77%)
(65%)
(-)
6
6
10 (R=4-Cl)
10
1 h - 0 oC
1 h - RT
11 (86%)
11 (94%)
14 (78%)
14 (93%)
16 (75%)
19 (52%)
19 (68%)
12 (R=4-Br)
12
1 h - 0 oC
4 min - RT
1 h - RT
13d
13d
15 (R=4-F)
17 (R=4-Me)
1 h - 0 oC
1 h - RT
18 (28%)
18 (27%)e
20 (5%)
5 (15%)
10 17
11 1 (R=H)
12 1
1 h - 0 oC
1 h - RT
3
3
(5%)
4
4
(57%)
(34%)
(31%)
13 21 (R=4-CO2Me) 10 min – RTf
14 21
24 h - RT
1 h - 0 oCg
24 h – RTh
1 h – RTi
22 (74%)
(74%)
(-)
15 23 (R=4-NO2)
16 23
(-)
17 24 (R=5-OMe)
18 24j
(-)
24 h - RT
6 min – RTk
1 h - 0 oC
1 h - RT
25 (51%)
(51%)
(9%)
19 26 (R=5-Cl)
20 26
28 (9%)
27 (56%)
27 (52%)
30 (67%)
30 (55%)
33 (21%)
33 (31%)
28 (27%)
28 (31%)
31 (28%)
31 (29%)
34 (22%)
34 (26%)
(83%)
(83%)
(95%)
(84%)
(63%)
(57%)
21 26
22 29 (R=5-Br)
23 29
10 min - RT
1 h - RT
24 32 (R=5-Me)
25 32
1 h - 0 oC
10 min - RT
35 (20%)
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Table 2. Base mediated formation of benzimidazoles under Conditions A continued.
Entry
Enamine
Temp/timea
Alkoxybenzimidazolesb
Σ (%)c
26 36 (R=OMe)
1 h - 0 oC
7d
7d
37 (78%)
(78%)
27 36
2 min - RT
37 (84%)
38 (11%)l
(95%)
28 39 (R=4-Br)
29 39
1 h - 0 oC
13 (22%)
13 (92%)
40 (22%)
41 (13%)
(57%)
(92%)
38 min - RT
a) 3.15 equivalents of NaH and MeI were used. The Time/Temp is the time elapsed before addition of MeI and the
temperature of the reaction mixture for the addition. b) Isolated yields of pure products after chromatography
unless stated as ~%. The ~% are yields calculated from the 1H NMR spectrum of an inseparable mixture. c) Total
yield of benzimidazole(s) isolated. d) Trace amount of the compound was observed in the 1H NMR of the crude
reaction mixture. e) Trace amount of 17 was observed in the 1H NMR spectrum. f) 4-Carbomethoxy-N-methyl-N-(2-
methyl-1-propen-1-yl)-2-nitroaniline, the N-methylation product of 21, was isolated in 62% yield. g) 2,4-Dinitro-N-
methyl-N-(2-methyl-1-propen-1-yl)aniline, the N-methylation product from 23, was isolated in 85% yield. h) No
product or unreacted 23 was observed. i) 5-Methoxy-2-nitro-N-methylaniline8 was isolated in 55% yield. j) 5.0
Equivalents of NaH and 3.9 equivalents of MeI were used. k) 5-Chloro-N-methyl-N-(2-methyl-1-propen-1-yl)-2-
nitroaniline, the N-methylation product of 26, was isolated in 52% yield. l) Trace amount of 7 was observed in the
1H NMR spectrum.
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The feasibility of a selective formation of mono-methylated benzimidazoles was evaluated next
using Conditions B. All enamines, but the 4-nitro-substituted enamine 23, were treated in
sequence with NaH and MeI under Conditions B and the results are summarized in Table 3. In
general, cyclizations under Conditions B were not as selective as the reaction of the 4-methoxy-
substituted enamine 6 to give 9 (See Table 1, entry 4 and Table 3, entry 1). However, cyclization
to produce a benzimidazole(s) occurred in all cases. For all enamines examined apart from the 4-
carbomethoxy- and the 5-methoxy-substituted compounds 21 and 24, all reactions furnished
mono-methylated benzimidazoles in 45-74% yield as the major product in addition to minor
amounts of either 2H-N-methoxybenzimidazoles (2-21%) or dimethylated benzimidazoles (15-
22%). In contrast to the reactions performed under Conditions A, the position of and the
electronic properties of the substituents on the aromatic ring had little effect on the product
distribution. For enamines 21 and 24, as was observed under Conditions A, extended reaction
times were required prior to the addition of methyl iodide and only 2H-N-
methoxybenzimidazoles were isolated (entries 7-10).
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Table 3. Base mediated formation of N-alkoxybenzimidazoles under Conditions B.
Entrya Enamine
Alkoxybenzimidazolesb
Σ (%)c
1
1 (R=H)
5 (55%)d
9 (~74%)
42 (59%)
43 (68%)
44 (56%)
20 (~45%)
(55%)
(76%)
(79%)
(90%)
(72%)
(55%)
(-)
2
6 (R=4-OMe)
10 (R=4-Cl)
12 (R=4-Br)
15 (R=4-F)
17 (R=4-Me)
21 (R=4-CO2Me)e
21f
7 (~2%)
3
11 (20%)
14 (22%)
16 (15%)
4
5
6
18 (~11%)
22 (73%)
25 (64%)
7
8
(73%)
(-)
9
24 (R=5-OMe)g
24f
10
11
12
13
(64%)
(70%)
(79%)
(61%)
26 (R=5-Cl)
29 (R=5-Br)
32 (R=5-Me)
28 (15%)
31 (16%)
45 (55%)
46 (63%)
35 (61%)
14
15
36 (R=OMe)
39 (R=4-Br)
37 (19%)
38 (51%)
41 (52%)
(70%)
(74%)
13 (22%)
a) Conditions B: 2.1 equivalents of NaH and 1.05 equivalents of MeI. The mixture was stirred for 1 h at ambient
temperature then cooled to 0 oC prior to addition of MeI unless otherwise stated. b) Isolated yields of pure products
after chromatography unless stated as ~%. The ~% are yields calculated from the 1H NMR spectrum of an
inseparable mixture. c) Total yield of benzimidazole(s) isolated. d) Trace amount of 3 was observed in the 1H NMR
spectrum. e) A ~3:1 mixture of 4-carbomethoxy-N-methyl-N-(2-methyl-1-propen-1-yl)-2-nitroaniline and 21 was
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observed in the 1H NMR of the crude reaction mixture. f) The base substrate mixture was stirred for 24 h before
addition of MeI. g) No product or starting material was observed.
The formation of 2H-benzimidazoles, wherein only the α-carbon of the enamine was retained in
the product, involves a carbon-carbon bond fission at some point during the reaction. For the
majority of enamines examined, a three-carbon unit is lost probably in the form of acetone (see
mechanistic discussion below). Neither acetone nor acetophenone or cyclohexanone, the
anticipated by-products from enamines 36 and 39, were recovered after chromatographic
purification. This is probably due to evaporative loss upon removal of solvents. In order to
isolate, characterize, and quantify any potential by-product derived from carbon-carbon bond
cleavage to form 2H-benzimidazoles, enamine 47 derived from 2,2-diphenylethanal and 4-
methoxy-2-nitroaniline was prepared. Treatment of 47 with NaH-MeI under Conditions A gave
rise to two products, the mono alkylated benzimidazole 48 as the major product and a small
amount of impure benzophenone (49) (Scheme 3). Gratifyingly, when the solvent and base
system described by Gardiner et al3b was used (t-BuOH/t-BuOK), an almost quantitative yield of
benzophenone (49) was isolated in addition to 2H-benzimidazole 7 in 78% yield.
Scheme 3 Synthesis of N-methoxybenzimidazole 48 and benzophenone (49).
47
47
NaH in DMSO, RT, 2 h
48 (89%)
49 (<9%)
49 (97%)
t-BuOK in t-BuOH, RT, 24 h
7 (78%)
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In addition to methyl iodide, a small selection of electrophiles including benzyl bromide, allyl
bromide, diiodomethane, propargyl bromide, and 3-bromo-1-butyne were examined using
enamine 6 as the substrate (Table 4). Moderate yields (40-69%) of N-oxygenated
benzimidazoles were isolated from these reactions. The reaction of 6 with a base and
diiodomethane is interesting in that a ring is formed between the benzimidazole oxygen and the
side chain (entry 5). Less reactive electrophiles such as alkyl bromides did not furnish any
isolable amounts of products.
Table 4. Base mediated formation of N-oxygenated benzimidazoles from enamine 6.
Entry Temp/timea Electrophile (R-X)
Alkoxybenzimidazolesb
Σ (%)c
1
2
3
4
5
6
7
8
1 h - 0 oC
Bn-Br
50 (38%)
50 (19%)
53 (14%)
53 (59%)
55 (40%)
51 (29%)
51 (50%)
(67%)
(69%)
2 min - RT
1 h - 0 oC
Bn-Br
Allyl-Br
Allyl-Br
CH2I2
52 (~5%)
56 (6%)
54 (~31%) (50%)
(59%)
1 min - RT
2 min - RT
1 min - RT
1 h - 0 oC
(40%)
Propargyl-Br
57 (47%)
59 (41%)
59 (66%)
(53%)
(50%)
(66%)
3-Bromo-1-butyne 58 (9%)
2 min - RT
3-Bromo-1-butyne
a) Conditions A: 3.15 equivalents of NaH and R-X. The Time/Temp is the time before addition of R-X and the
temperature for the addition. b) Isolated yields of pure products after chromatography unless stated as ~%. The ~%
are yields calculated from the 1H NMR spectrum of an inseparable mixture. c) Total yield of benzimidazole(s)
isolated.
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Finally, enamine 6 was treated with NaH in DMSO followed by addition of acetyl chloride. Two
products were obtained in low isolated yields from this reaction, diacetoxybenzimidazole 60 and
acetoxybenzimidazole 61 having an unsaturated substituent in the 2-position (Scheme 4). The
latter product is probably formed by elimination of acetic acid from 60.
Scheme 4. Reaction of 6 with acetyl chloride.
6
60 (18%)
61 (6%)
The base-mediated transformation to yield N-alkoxybenzimidazoles is limited to enamines
derived from condensation of α-branched aldehydes and 4- or 5-substituted-2-nitroanilines.
Attempts to prepare enamines from 2-nitroanilines and simple unbranched aliphatic aldehydes,
for example propanal and hexanal, were unsuccessful affording complex mixtures of inseparable
products. In addition, 3- and 6-substituted 2-nitrobenzeneamines did not form enamines with
any aldehyde using the conditions presented herein, even under more forced reaction
conditions. Only unreacted 2-nitroaniline starting materials were isolated from these reactions.
Mechanistic considerations
The overall transformation presented above to afford N-oxygenated benzimidazoles can
mechanistically be rationalized as follows. Deprotonation of 1 would form an anion and two of
several possible resonance forms, 62 and 63, are depicted in Scheme 5. 1,7-Electrocyclization of
63 would furnish 64, which may undergo ring opening to form the nitroso-imine 65. 1,5-
Electrocyclization of 65 to give 66 is plausible. While electrocyclization of imines derived from 2-
nitrosoaniline and aldehydes are rare, the formation of 2-phenyl-1-hydroxybenzimidazole from
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in situ reaction of 2-nitrosoaniline and benzaldehyde has been described.9 Aromatization of
intermediate 66 would furnish N-alkoxybenzimidazole 67 by loss of acetone or
dialkoxybenzimidazole 68 via deprotonation. The timing of the alkylation is unclear since it is
plausible that alkylation can occur both prior to and after aromatization. The proposed
mechanism suggests that two equivalents of a base is required for the transformation of 1 to give
4 and 5, one for the initial deprotonation to give 62/63 and one for deprotonation -
aromatization of 66 to give 68. Although 2.15 equivalents proved optimum for the formation of
the mono-alkylated benzimidazoles, it is unclear why an additional equivalent of base was
required to maximize the yield of dialkylated benzimidazoles.
Scheme 5. Proposed mechanism for the formation of the N-oxygenated benzimidazoles 3-5.
62
63
64
65
66
67
68
3
4
5
The mechanism outlined in Scheme 5 is supported by a limited number of related reactions
reported in the literature. For example, Nyerges et al proposed a 1,7-electrocyclization of
azomethine ylide (69), as a key mechanistic step toward indazole-N-oxide 72 (Scheme 6).10,11
The authors suggested a ring-contraction of the cylization intermediate 70 with concurrent loss
of formaldehyde to give the final product without any intermediates. However loss of
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formaldehyde to give nitroso-imine 71 followed by a 1,5-electrocyclization as shown in Scheme
6 would also furnish 72. The reactions in Schemes 3-6 are the result of an intramolecular
oxidation-reduction wherein the alkyl-substituent on the amino group is oxidized to an alkoxide
at the same time the nitro group is reduced to a nitroso group followed by further steps. We have
reported a related palladium catalyzed reductive cyclization of 2-nitrostyrenes in the presence of
a base to give 2-unsubstituted or 2-oxygenated indoles.12 A similar mechanistic rational was
proposed to explain the side-chain oxygenation.
Scheme 6 Proposed mechanism for the formation of indazole-N-oxides.
69
70
71
72
In summary, a synthetic route to N-alkoxybenzimidazoles via a base mediated cyclization of
enamines α-branched aldehydes with 4- or 5-
substituted 2-nitroaniline has been developed. Cyclization to afford N-alkoxybenzimidazoles in
the presence of an alkyl halide was realized in moderate to excellent yield in all but one case.
Supporting Information
Supplementary information associated withthis article including all experimental
procedures and 1H and 13C NMR spectra of new compounds can befound in the online
version, at http://dx.doixxxxxxxxx
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Acknowledgements
We gratefully acknowledge the C. Eugene Bennett Department of Chemistry for support. The
National Science Foundation-MRI program is also acknowledged for the funding of a 400 MHz
NMR system (CHE-1228366). The authors would like to thank Mr. Mahdiar Khakinejad for HRMS
analyses.
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General Procedures. NMR spectra were determined in CDCl3 at 600 or 400 MHz (1H NMR) and
at 150 or 100 MHz (13C NMR). The chemical shifts are expressed in δ values relative to SiMe4 (0.0
ppm, 1H and 13C) or CDCl3 (77.0 ppm, 13C) internal standards. The multiplicity of each resonance
observed in the 1H NMR spectra are reported as, s = singlet; d = doublet; t = triplet; q = quartet; m
= multiplet.
Dichloromethane was purified/dried via two consecutive columns composed of activated
alumina on a Glass Contours solvent purification system. Anhydrous dimethylsulfoxide, N-
methylpyrrolidinone, and N,N-dimethylformamide were used as received. Chemicals prepared
according to literature procedures have been footnoted the first time used; all other reagents
were obtained from commercial sources and used as received. All reactions were performed
under a nitrogen atmosphere in oven-dried glassware unless otherwise stated. Solvents were
removed from reaction mixtures and products on a rotary evaporator at water aspirator
pressure. Melting points are uncorrected.
4-Bromo-2-nitro-N-(2-methyl-1-propen-1-yl)benzenamine (12). Treatment of a solution of
4-bromo-2-nitrobenzenamine (1.04 g, 4.78 mmol) and 2-methylpropanal (414 mg, 5.74 mmol) in
dichloromethane (DCM, 12 mL) at ambient temperature under a nitrogen atmosphere in the
presence of 4 Å molecular sieves (3 g), as described for 24 (24 h), gave after work up and
chromatography, (hexane/EtOAc, 95:5), 12 (726 mg, 2.68 mmol, 56%) as a violet solid. mp=119-
120 °C; 1H NMR (400 MHz, CDCl3) δ 9.55 (d, J=8.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.47 (dd, J=9.2,
2.4 Hz, 1H), 6.93 (d, J=9.6 Hz, 1H), 6.20 (d, J=9.6 Hz, 1H), 1.81 (s, 3H), 1.78 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 140.3, 138.8, 128.8, 119.9, 117.9, 116.0, 107.6, 22.5, 16.8; IR (ATR) 2912, 1564,
1340, 1165 cm-1; HRMS (ESI) calcd for C10H12BrN2O2 (M+H+) 271.0082, found 271.0078.
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4-Fluoro-2-nitro-N-(2-methyl-1-propen-1-yl)benzenamine (15). Treatment of a solution of
4-fluoro-2-nitrobenzenamine (845 mg, 5.41 mmol) with 2-methylpropanal (390 mg, 5.41 mmol)
in DCM (12 mL), in the presence of 5 Å molecular (12 g), at ambient temperature under a
nitrogen atmosphere, as described for 24, (24 h), gave after work up and chromatography
(hexane/EtOAc, 97:3), 15 (788 mg, 3.75 mmol, 69%) as a reddish-brown solid. mp=79-80 °C; 1H
NMR (400 MHz, CDCl3) δ 9.48 (d, J=7.6 Hz, 1H), 7.87 (dd, J=8.8, 2.8 Hz, 1H), 7.27-7.22 (ddd, J=9.6,
6.4, 2.4 Hz, 1H), 7.02 (dd, J=9.6, 4.8 Hz, 1H), 6.21 (d, with further fine splitting J=9.6 Hz, 1H), 1.81
(s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.0 (d, JC-F=239.0 Hz), 138.6 (d, JC-F=1.0 Hz),
130.5 (d, JC-F=8.0 Hz), 124.9 (d, JC-F=24 Hz), 119.2, 118.2, 115.7 (d, JC-F=8.0 Hz), 111.8 (d, JC-F=26.0
Hz), 22.3, 16.7; IR (ATR) 1580, 1519, 1404, 1185, 1158, 1112 cm-1; HRMS (ESI) C10H12FN2O2
(M+H+) 211.0883, found 211.0897.
5-Methoxy-2-nitro-N-(2-methyl-1-propen-1-yl)benzenamine (24). To a solution of 5-
methoxy-2-nitrobenzenamine (1.00 g, 5.95 mmol) and 2-methylpropanal (515 mg, 7.14 mmol) in
dichloromethane (DCM, 12 mL) at ambient temperature under a nitrogen atmosphere was added
4 Å molecular sieves (3 g, activated by heating at 120 °C under vacuum overnight, then stored
under nitrogen). The reaction mixture was allowed to sit without agitation or stirring for 48 h.
The mixture was then filtered and the sieves were washed with DCM (20 mL). The filtrate was
concentrated under reduced pressure and the resulting residue was purified by chromatography
(hexane/EtOAc, 9:1) to give 24 (484 mg, 2.18 mmol, 37%) as a red solid. mp=83-84 °C; 1H NMR
(600 MHz, CDCl3) δ 9.86 (d, J=7.2 Hz, 1H), 8.14 (d, J=9.6 Hz, 1H), 6.32 (d, J=3.0 Hz, 1H), 6.29 (dd,
J=9.6, 2.4 Hz, 1H), 6.20 (dpent, J=9.6, 1.2 Hz, 1H), 3.88 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H); 13C NMR
20

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(150 MHz, CDCl3) δ 165.7, 143.5, 129.0, 126.0, 119.0, 118.0, 106.1, 95.0, 55.7, 22.5, 16.8; IR
(ATR) 2923, 1616, 1585, 1497, 1239 cm-1; HRMS (ESI) calcd for C11H14N2O3Na (M+Na+)
245.0902, found 245.0896.
5-Bromo-2-nitro-N-(2-methyl-1-propen-1-yl)benzenamine (29). Treatment of a solution of
5-bromo-2-nitrobenzenamine (455 mg, 2.10 mmol) with 2-methylpropanal (182 mg, 2.52 mmol)
in benzene (6 mL), in the presence of 4 Å molecular sieves (4 g), at ambient temperature under a
nitrogen atmosphere, as described for 24 (24 h), gave after work up and chromatography
(hexane/EtOAc, 95:5), 29 (416 mg, 1.534 mmol, 73%) as a red solid. mp=94-95 °C; 1H NMR (600
MHz, CDCl3) δ 9.56 (d, J=7.2 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 6.81 (dd, J=9.0,
1.8 Hz, 1H), 6.18 (d with further fine splitting, J=9.6 Hz, 1H), 1.83 (s, 3H), 1.79 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 141.8, 131.6, 130.7, 128.1, 120.7, 119.8, 117.8, 117.0, 22.5, 16.9; IR (ATR)
3495, 3381, 1616, 1560, 1489, 1218 cm-1; HRMS (ESI) calcd for C10H12BrN2O2 (M+H+) 271.0082,
found 271.0078.
5-Methyl-2-nitro-N-(2-methyl-1-propen-1-yl)benzenamine (32). Treatment of a solution of
5-methyl-2-nitrobenzenamine (200 mg, 1.31 mmol) and 2-methylpropanal (114 mg, 1.58 mmol)
in benzene (3 mL), in the presence of 4 Å molecular sieves (1 g) at ambient temperature under a
nitrogen atmosphere, as described for 24 (24 h), gave after work up and chromatography
(hexane/EtOAc, 95:5), 32 (106 mg, 0.514 mmol, 39%) as a red solid. mp=75-76 °C; 1H NMR (600
MHz, CDCl3) δ 9.63 (d, J=7.8 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 6.51 (dd, J=9.0, 1.2 Hz,
1H), 6.27 (d with further fine splitting, J=9.0 Hz, 1H), 2.35 (s, 3H), 1.82 (s, 3H), 1.79 (s, 3H); 13
C
NMR (150 MHz, CDCl3) δ 147.7, 141.4, 129.9, 126.8, 118.5, 118.4, 118.2, 113.8, 22.5, 22.1, 16.8; IR
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(ATR) 1618, 1578, 1332, 1210, 1183 cm-1; HRMS (ESI) calcd for C11H15N2O2 (M+H+) 207.1133,
found 207.1128.
4-Bromo-2-nitro-N-(2-phenyl-1-propen-1-yl)benzenamine (39). Treatment of a solution of
4-bromo-2-nitrobenzenamine (430 mg, 1.98 mmol) with 2-phenylpropanal (239 mg, 1.78 mmol)
in DCM (7 mL), in the presence of 5 Å molecular sieves (3.5 g), at ambient temperature under a
nitrogen atmosphere, as described for 24 (24 h), gave after work up and chromatography
(hexane/EtOAc, 95:5), 36 (446 mg, 1.34 mmol, 67%) as a violet solid. mp=106-107 °C; 1H NMR
(400 MHz, CDCl3) δ 9.93 (d, J=10.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.56 (dd, J=9.2, 2.4 Hz, 1H),
7.42-7.34 (m, 4H), 7.29-7.25 (m, 1H), 7.09 (d, J=9.2 Hz, 1H), 6.87 (dq, J=10.4, 1.2 Hz, 1H), 2.21 (d,
J=1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9, 139.4, 138.9, 132.7, 129.0, 128.5, 126.8, 125.3,
120.6, 120.5, 116.0, 108.8, 14.7; IR (ATR) 1618, 1564, 1175, 1126, 749 cm-1; HRMS (ESI) calcd for
C15H14BrN2O2 (M+H+) 333.0238, found 333.0234.
A detailed experimental procedure for the experiment in Entry 1 in Table 1 is shown below. All
other entries in Tables 1-3 are slight variations of this procedure. Detailed experimental
procedures for all entries discussed can be found in the Supporting Information file associated
with this paper.
Table 2, Entry 1
1-Methoxybenzimidazole (3),13 1-Methoxy-2-(2-methoxy-2-propyl)benzimidazole (4), and
2-(2-Hydroxy-2-propyl)-1-methoxybenzimidazole (5). A mixture of 2-nitro-N-(2-methyl-1-
propen-1-yl)benzenamine (1)14 (160 mg, 0.833 mmol) and sodium hydride15 (NaH, 74.4 mg, 3.10
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mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at ambient temperature under a
nitrogen atmosphere. After stirring for 1 h, the mixture was cooled to 0 °C and methyl iodide
(379 mg, 2.67 mmol) was added via a syringe. The reaction vessel was removed from the cold
bath and stirred for 1 h. The resulting mixture was diluted with EtOAc (20 mL), washed with
water (5x15 mL), dried (MgSO4), and filtered. The solvents were removed from the filtrate under
reduced pressure and the resulting residue was purified by chromatography (hexane/EtOAc, 7:3
then 3:7) to give, in order of elution 4 (105 mg, 0.477 mmol, 57%) as a colorless oil, 5 (25.3 mg,
0.123 mmol, 15%) as a white solid, and 3 (6.3 mg, 0.043 mmol, 5%) as a colorless oil.
Analytical data for all compounds:
1-Methoxybenzimidazole (3). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.78 (d,
J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.34 (td, J=7.2, 1.2 Hz, 1H), 7.29 (td, J=8.0, 1.2 Hz, 1H), 4.17
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.4, 137.4, 129.2, 123.6, 122.5, 120.9, 108.3, 67.2; IR
(ATR) 1476, 1449, 1318, 1074, 962 cm-1; HRMS (ESI) calcd for C8H9N2O (M+H+) 149.0715, found
149.0710.
1-Methoxy-2-(2-methoxy-2-propyl)benzimidazole (4). Colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.32 (td, J=7.2, 1.2 Hz, 1H), 7.26 (td, J=7.2,
1.2 Hz, 1H), 4.20 (s, 3H), 3.19 (s, 3H), 1.80 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 151.3, 136.9,
131.4, 123.4, 122.2, 120.4, 108.3, 74.5, 65.2, 51.3, 24.8; IR (ATR) 1244, 1176, 1151, 1066, 969 cm-
1; HRMS (ESI) calcd for C12H17N2O2 (M+H+) 221.1290, found 221.1285.
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1-Methoxy-2-(2-hydroxy-2-propyl)benzimidazole (5). White solid; mp=121-122 oC; 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.31 (td, J=7.2, 1.2 Hz, 1H), 7.26
(td, J=8.0, 1.6 Hz, 1H), 4.22 (s, 3H), 3.51 (br s, 1H), 1.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
154.2, 136.9, 131.2, 123.3, 122.5, 120.4, 108.5, 69.8, 65.7, 28.8; IR (ATR) 3240, 1438, 1359, 1234,
1176, 1147 cm-1; HRMS (ESI) calcd for C11H15N2O2 (M+H+) 207.1133, found 207.1118.
1,6-Dimethoxybenzimidazole (7). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.64
(d, J=9.6 Hz, 1H), 6.93-6.90 (m, 2H), 4.17 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3,
136.6, 133.9, 129.9, 121.6, 112.4, 91.3, 67.0, 55.8; IR (ATR) 1493, 1236, 1020, 815 cm-1; HRMS
(ESI) calcd for C9H11N2O2 (M+H+) 179.0820, found 179.0814.
1,6-Dimethoxy-2-(2-methoxy-2-propyl)benzimidazole (8). Pale yellow oil; 1H NMR (400
MHz, CDCl3) δ 7.61 (d, J=9.6 Hz, 1H), 6.88 (dd, J=7.2, 2.4 Hz, 1H), 6.87 (s, 1H), 4.17 (s, 3H), 3.88 (s,
3H), 3.16 (s, 3H), 1.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.2, 150.5, 132.1, 131.3, 121.1,
111.8, 91.4, 74.5, 65.0, 55.8, 51.3, 24.9; IR (ATR) 2929, 1738, 1215, 1063, 817 cm-1; HRMS (ESI)
calcd for C13H19N2O3 (M+H+) 251.1395, found 251.1389.
2-(2-Hydroxy-2-propyl)-1,6-dimethoxybenzimidazole (9). Data from a 37:1 mixture of 9 and
7: White solid; mp=119-120 oC, 1H NMR δ 7.59 (d, J=8.6 Hz, 1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.87
(d, J=2.2 Hz, 1H), 4.21 (s, 3H), 3.89 (s, 3H), 3.26 (br s, 1H), 1.76 (s, 6H); 13C NMR δ 157.1, 153.4,
131.8, 131.4, 121.0, 111.8, 92.0, 69.8, 65.5, 55.9, 28.8; IR (neat) 3234, 1625, 1497, 1242, 1217,
1178, 1147, 1018, 956, 823 cm-1; HRMS (ESI) calcd for C12H17N2O3 (M+H+) 237.1239, found
237.1229.
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6-Chloro-1-methoxy-2-(2-methoxy-2-propyl)benzimidazole (11). Orange solid; mp=66-67
oC; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.19 (dd, J=8.4, 1.6
Hz, 1H), 4.16 (s, 3H), 3.16 (s, 3H), 1.76 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.4, 135.5, 132.1,
129.4, 123.1, 121.4, 108.4, 74.5, 65.5, 51.3, 24.8; IR (ATR) 2944, 1677, 1496, 1340, 1268, 1228
cm-1; HRMS (ESI) calcd for C12H16ClN2O2 (M+H+) 255.0900, found 255.0893.
6-Bromo-1-methoxybenzimidazole (13). White solid; mp=46-47 oC; 1H NMR (400 MHz, CDCl3)
δ 8.05 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.38 (dd, J=8.4, 1.6 Hz, 1H), 4.17 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 138.3, 138.1, 130.3, 126.0, 122.3, 117.1, 111.5, 67.4; IR (ATR)
1462, 1347, 1220, 1086, 952 cm-1; HRMS (ESI) calcd for C8H8BrN2O (M+H+) 226.9820, found
226.9814.
6-Bromo-1-methoxy-2-(2-methoxy-2-propyl)benzimidazole (14). Orange oil; 1H NMR (600
MHz, CDCl3) δ 7.57 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 1.8 Hz, 1H), 4.15 (s, 3H), 3.15 (s,
3H), 1.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 152.3, 136.0, 132.6, 125.8, 121.8, 116.9, 111.5,
74.6, 65.6, 51.4, 24.8; IR (ATR) 2941, 1461, 1355, 1240, 1177 cm-1; HRMS (ESI) calcd for
C12H16BrN2O2 (M+H+) 299.0395, found 299.0390.
6-Fluoro-1-methoxy-2-(2-methoxy-2-propyl)benzimidazole (16). Pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.62 (dd, J=8.8, 4.8 Hz, 1H), 7.07 (dd, J=8.0, 2.4 Hz, 1H), 6.95 (td, J=9.6, 2.4 Hz,
1H), 4.13 (s, 3H), 3.14 (s, 3H), 1.73 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.9 (d, JC-F=241.0 Hz),
152.2 (d, JC-F=3.0 Hz), 133.2, 131.5 (d, JC-F=13.0 Hz), 121.4 (d, JC-F=10.0 Hz), 110.8 (d, JC-F=25.0 Hz),
95.0 (d, JC-F=28.0 Hz), 74.4, 65.2, 51.3, 24.7; IR (ATR) 1486, 1448, 1172, 1067, 965, 811 cm-1;
HRMS (ESI) calcd for C12H16FN2O2 (M+H+) 239.1196, found 239.1191.
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1-Methoxy-6-methylbenzimidazole (18). Colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.02 (br s,
1H), 7.65 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 4.17 (s, 3H), 2.51 (s, 3H); 13
NMR (100 MHz, CDCl3) δ 137.5, 137.0, 133.8, 129.4, 124.2, 120.4, 108.1, 67.1, 21.7; IR (ATR)
2922, 1457, 1060, 965, 806 cm-1; HRMS (ESI) calcd for C9H11N2O (M+H+) 163.0871, found
163.0867.
C
1-Methoxy-2-(2-methoxy-2-propyl)-6-methylbenzimidazole (19). Colorless oil; 1H NMR
(600 MHz, CDCl3) δ 7.60 (d, J=8.4 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.06 (dd, J=8.4, 1.2 Hz, 1H), 4.15
(s, 3H), 3.15 (s, 3H), 2.48 (s, 3H), 1.76 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 150.8, 135.1, 133.6,
131.6, 123.9, 119.9, 108.1, 74.5, 65.1, 51.3, 24.9, 21.7; IR (ATR) 2947, 1242, 1176, 810 cm-1;
HRMS (ESI) calcd for C13H19N2O2 (M+H+) 235.1446, found 235.1441.
2-(2-Hydroxy-2-propyl)-1-methoxy-6-methylbenzimidazole (20). White solid; mp=99-100
oC; 1H NMR (600 MHz, CDCl3) δ 7.58 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.08 (dd, J=8.4, 1.2 Hz, 1H),
4.21 (s, 3H), 3.44 (br s, 1H), 2.50 (s, 3H), 1.76 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.8, 135.0,
133.5, 131.4, 124.1, 119.9, 108.3, 69.8, 65.6, 28.8, 21.8; IR (ATR) 3241, 1145, 951, 815 cm-1;
HRMS (ESI) calcd for C12H17N2O2 (M+H+) 221.1290, found 221.1285.
Methyl 1-methoxybenzimidazole-6-carboxylate (22). White solid; mp=126-127 oC; 1H NMR
(600 MHz, CDCl3) δ 8.23 (br s, 1H), 8.19 (s, 1H), 7.99 (dd, J=8.4, 1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H),
4.22 (s, 3H), 3.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.0, 142.6, 140.0, 129.0, 125.6, 123.9,
120.7, 110.9, 67.7, 52.2; IR (ATR) 1698, 1441, 1320, 1280, 1226 cm-1; HRMS (ESI) calcd for
C10H11N2O3 (M+H+) 207.0769, found 207.0763.
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1,5-Dimethoxybenzimidazole (25). Colorless oil; 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.35
(d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.4, 2.4 Hz, 1H), 4.15 (s, 3H), 3.85 (s, 3H); 13
C
NMR (150 MHz, CDCl3) δ 156.4, 140.3, 137.4, 123.9, 114.1, 108.8, 102.7, 67.2, 55.7; IR (ATR)
1213, 1125, 969, 803 cm-1; HRMS (ESI) calcd for C9H11N2O2 (M+H+) 179.0820, found 179.0820.
5-Chloro-1-methoxybenzimidazole (27). Yellow oil; 1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H),
7.75 (d, J=1.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.29 (dd, J=9.0, 1.8 Hz, 1H), 4.16 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 140.0, 138.5, 128.1, 127.8, 124.1, 120.5, 109.1, 67.3; IR (ATR) 1457, 1309,
1054, 965, 898 cm-1; HRMS (ESI) calcd for C8H7ClN2O (M+Na+) 205.0144, found 205.0139.
5-Chloro-1-methoxy-2-(2-methoxy-2-propyl)benzimidazole (28). Yellow oil; 1H NMR (600
MHz, CDCl3) δ 7.71 (d, J=1.2 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4, 1.8 Hz, 1H), 4.18 (s,
3H), 3.18 (s, 3H), 1.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.7, 137.8, 130.2, 128.0, 124.0,
120.3, 109.2, 74.6, 65.5, 51.4, 24.8; IR (ATR) 2938, 1700, 1608, 1575, 1493, 1245 cm-1; HRMS
(ESI) calcd for C12H16ClN2O2 (M+H+) 255.0900, found 255.0901.
5-Bromo-1-methoxybenzimidazole (30). Faint yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.05 (s,
1H), 7.91 (d, J=1.6 Hz, 1H), 7.43 (dd, J=8.8, 2.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 4.16 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 140.6, 138.4, 128.2, 126.8, 123.7, 115.6, 109.7, 67.4; IR (ATR) 1454,
1308, 1175, 1066, 729 cm-1; HRMS (ESI) calcd for C8H8BrN2O (M+H+) 226.9820, found 226.9815.
5-Bromo-1-methoxy-2-(2-methoxy-2-propyl)benzimidazole (31). Red oil; 1H NMR (400
MHz, CDCl3) δ 7.87 (d, J=1.6 Hz, 1H), 7.41 (dd, J=8.4, 1.6 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.17 (s,
27

ACCEPTED MANUSCRIPT
3H), 3.17 (s, 3H), 1.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.6, 138.3, 130.5, 126.6, 123.4,
115.2, 109.6, 74.6, 65.5, 51.4, 24.8; IR (ATR) 1454, 1308, 1246, 1176, 1066 cm-1; HRMS (ESI)
calcd for C12H16BrN2O2 (M+H+) 299.0395, found 299.0376.
1-Methoxy-5-methylbenzimidazole (33). Orange oil; 1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H),
7.56 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.17 (s, 3H), 2.48 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 139.9, 137.4, 132.3, 127.4, 125.2, 120.6, 107.9, 21.5; IR (ATR) 2931, 1686, 1607,
1523, 1341, 1077 cm-1; HRMS (ESI) calcd for C9H11N2O (M+H+) 163.0871, found 163.0866.
1-Methoxy-5-methyl-(2-methoxy-2-propyl)benzimidazole (34). Orange oil; 1H NMR (400
MHz, CDCl3) δ 7.53 (br s, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.14 (dd, J=8.0, 0.8 Hz, 1H), 4.17 (s, 3H), 3.17
(s, 3H), 2.47 (s, 3H), 1.78 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 151.2, 137.4, 132.0, 129.6, 124.9,
120.2, 107.9, 74.6, 65.2, 51.4, 25.0, 21.5; IR (ATR) 2939, 1455, 1314, 1248, 1067 cm-1; HRMS
(ESI) calcd for C13H19N2O2 (M+H+) 235.1446, found 235.1439.
1-Methoxy-(2-hydroxy-2-propyl)-5-methylbenzimidazole (35). White solid; mp=99-100 oC;
1H NMR (400 MHz, CDCl3) δ 7.50 (br s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.14 (dd, J=8.4, 1.2 Hz, 1H),
4.20 (s, 3H), 3.45 (br s, 1H), 2.47 (s, 3H), 1.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.2, 137.3,
132.3, 129.3, 124.7, 120.1, 108.0, 69.7, 65.6, 28.7, 21.5; IR (ATR) 3242, 1372, 1309, 1236, 1145
cm-1; HRMS (ESI) calcd for C12H17N2O2 (M+H+) 221.1290, found 221.1285.
1,6-Dimethoxy-2-(1-methoxycyclohexyl)benzimidazole (37). Colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.62 (d, J=9.6 Hz, 1H), 6.88 (dd, J=9.6, 2.4 Hz, 1H), 6.87 (s, 1H), 4.16 (s, 3H), 3.89 (s,
28

ACCEPTED MANUSCRIPT
3H), 3.10 (s, 3H), 2.34-2.31 (m, 2H), 2.16-2.10 (m, 2H), 1.76-1.64 (m, 2H), 1.62-1.56 (m, 3H),
1.42-1.35 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 157.0, 149.9, 131.8, 131.4, 120.9, 111.7, 91.3,
75.8, 64.9, 55.7, 50.4, 32.5, 25.5, 21.7; IR (ATR) 2944, 1739, 1450, 1365, 1207 cm-1; HRMS (ESI)
calcd for C16H23N2O3 (M+H+) 291.1708, found 291.1701.
1,6-Dimethoxy-2-(1-hydroxycyclohexyl)benzimidazole (38). White solid; mp=132-133 oC;
1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J=8.4, 1.2 Hz, 1H), 6.87 (dd, J=8.4, 2.4 Hz, 1H, 6.86 (s, 1H),
4.19 (s, 3H), 3.88 (s, 3H), 2.87 (br s, 1H), 2.17 (td, J=12.8, 4.0 Hz, 2H), 2.02-1.99 (m, 2H), 1.85-
1.77 (m, 2H), 1.72-1.62 (m, 3H), 1.42-1.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.0, 153.2,
131.7, 131.5, 121.0, 111.7, 91.8, 71.3, 65.5, 55.9, 36.1, 25.3, 21.6; IR (ATR) 3281, 2940, 1504,
1451, 1435, 1237 cm-1; HRMS (ESI) calcd for C15H21N2O3 (M+H+) 277.1552; found: 277.1547.
6-Bromo-1-methoxy-(1-methoxy-1-phenylethyl)benzimidazole (40). Orange oil; 1H NMR
(400 MHz, CDCl3) δ 7.67 (dd, J=8.8, 0.4 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.8, 1.6 Hz, 1H),
7.42-7.40 (m, 2H), 7.35-7.24 (m, 3H), 3.53 (s, 3H), 3.29 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.1, 144.0, 136.1, 128.2, 127.4, 125.9, 125.2, 122.0, 117.0, 111.6, 110.0, 78.3, 64.8,
51.4, 25.0; IR (ATR) 1437, 1373, 1245, 1185, 981, 792 cm-1; HRMS (ESI) calcd for C17H18N2O2
(M+H+) 361.0551, found 361.0549.
6-Bromo-(1-hydroxy-1-phenylethyl)-1-methoxybenzimidazole (41). Colorless oil; 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, J=8.4 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.48-7.46 (m, 2H), 7.39 (dd,
J=8.4, 1.6 Hz, 1H), 7.38-7.27 (m, 3H), 3.90 (br s, 1H), 3.39 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.2, 144.4, 136.0, 132.0, 128.6, 127.9, 126.1, 125.2, 122.0, 116.9, 111.5, 73.4, 65.0,
29